1 6585 135 TRPV4-MEDIATED ANTI-NOCICEPTIVE EFFECT OF SUBERANILOHYDROXAMIC ACID ON MECHANICAL PAIN. BIOLOGICAL EFFECTS OF SUBERANILOHYDROXAMIC ACID (SAHA) HAVE MAINLY BEEN OBSERVED IN THE CONTEXT OF TUMOR SUPPRESSION VIA EPIGENETIC MECHANISMS, BUT OTHER POTENTIAL OUTCOMES FROM ITS USE HAVE ALSO BEEN PROPOSED IN DIFFERENT FIELDS SUCH AS PAIN MODULATION. HERE, WE TRIED TO UNDERSTAND WHETHER SAHA MODULATES SPECIFIC PAIN MODALITIES BY A NON-EPIGENETIC UNKNOWN MECHANISM. FROM 24 H COMPLETE FREUND'S ADJUVANT (CFA)-INFLAMED HIND PAWS OF MICE, MECHANICAL AND THERMAL INFLAMMATORY PAIN INDICES WERE COLLECTED WITH OR WITHOUT IMMEDIATE INTRAPLANTAR INJECTION OF SAHA. TO EXAMINE THE ACTION OF SAHA ON SENSORY RECEPTOR-SPECIFIC PAIN, TRANSIENT RECEPTOR POTENTIAL (TRP) ION CHANNEL-MEDIATED PAIN INDICES WERE COLLECTED IN THE SAME MANNER OF INTRAPLANTAR TREATMENT. ACTIVITIES OF PRIMARILY CULTURED SENSORY NEURONS AND HETEROLOGOUS CELLS TRANSFECTED WITH TRP CHANNELS WERE MONITORED TO DETERMINE THE MOLECULAR MECHANISM UNDERLYING THE PAIN-MODULATING EFFECT OF SAHA. AS A RESULT, IMMEDIATE AND LOCALIZED PRETREATMENT WITH SAHA, AVOIDING AN EPIGENETIC INTERVENTION, ACUTELY ATTENUATED MECHANICAL INFLAMMATORY PAIN AND RECEPTOR-SPECIFIC PAIN EVOKED BY INJECTION OF A TRP CHANNEL AGONIST IN ANIMAL MODELS. WE SHOW THAT A COMPONENT OF THE MECHANISMS INVOLVES TRPV4 INHIBITION BASED ON IN VITRO INTRACELLULAR CA(2+) IMAGING AND ELECTROPHYSIOLOGICAL ASSESSMENTS WITH HETEROLOGOUS EXPRESSION SYSTEMS AND CULTURED SENSORY NEURONS. TAKEN TOGETHER, THE PRESENT STUDY PROVIDES EVIDENCE OF A NOVEL OFF-TARGET ACTION AND ITS MECHANISM OF SAHA IN ITS MODALITY-SPECIFIC ANTI-NOCICEPTIVE EFFECT AND SUGGESTS THE UTILITY OF THIS COMPOUND FOR PHARMACOLOGICAL MODULATION OF PAIN. 2019 2 2053 34 EPIGENETIC CONNECTIONS OF THE TRPA1 ION CHANNEL IN PAIN TRANSMISSION AND NEUROGENIC INFLAMMATION - A THERAPEUTIC PERSPECTIVE IN MIGRAINE? PERSISTENT REPROGRAMMING OF EPIGENETIC PATTERN LEADS TO CHANGES IN GENE EXPRESSION OBSERVED IN MANY NEUROLOGICAL DISORDERS. TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL SUBFAMILY A MEMBER 1 (TRPA1), A MEMBER OF THE TRP CHANNELS SUPERFAMILY, IS ACTIVATED BY MANY MIGRAINE TRIGGERS AND EXPRESSED IN TRIGEMINAL NEURONS AND BRAIN REGIONS THAT ARE IMPORTANT IN MIGRAINE PATHOGENESIS. TRP CHANNELS CHANGE NOXIOUS STIMULI INTO PAIN SIGNALS WITH THE INVOLVEMENT OF EPIGENETIC REGULATION. THE EXPRESSION OF THE TRPA1 ENCODING GENE, TRPA1, IS MODULATED IN PAIN-RELATED SYNDROMES BY EPIGENETIC ALTERATIONS, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS, AND EFFECTS OF NON-CODING RNAS: MICRO RNAS (MIRNAS), LONG NON-CODING RNAS, AND CIRCULAR RNAS. TRPA1 MAY CHANGE EPIGENETIC PROFILE OF MANY PAIN-RELATED GENES AS IT MAY MODIFY ENZYMES RESPONSIBLE FOR EPIGENETIC MODIFICATIONS AND EXPRESSION OF NON-CODING RNAS. TRPA1 MAY INDUCE THE RELEASE OF CALCITONIN GENE RELATED PEPTIDE (CGRP), FROM TRIGEMINAL NEURONS AND DURAL TISSUE. THEREFORE, EPIGENETIC REGULATION OF TRPA1 MAY PLAY A ROLE IN EFFICACY AND SAFETY OF ANTI-MIGRAINE THERAPIES TARGETING TRP CHANNELS AND CGRP. TRPA1 IS ALSO INVOLVED IN NEUROGENIC INFLAMMATION, IMPORTANT IN MIGRAINE PATHOGENESIS. THE FUNDAMENTAL ROLE OF TRPA1 IN INFLAMMATORY PAIN TRANSMISSION MAY BE EPIGENETICALLY REGULATED. IN CONCLUSION, EPIGENETIC CONNECTIONS OF TRPA1 MAY PLAY A ROLE IN EFFICACY AND SAFETY OF ANTI-MIGRAINE THERAPY TARGETING TRP CHANNELS OR CGRP AND THEY SHOULD BE FURTHER EXPLORED FOR EFFICIENT AND SAFE ANTIMIGRAINE TREATMENT. THIS NARRATIVE/PERSPECTIVE REVIEW PRESENTS INFORMATION ON THE STRUCTURE AND FUNCTIONS OF TRPA1 AS WELL AS ROLE OF ITS EPIGENETIC CONNECTIONS IN PAIN TRANSMISSION AND POTENTIAL IN MIGRAINE THERAPY. 2023 3 5977 37 TET1-TRPV4 SIGNALING CONTRIBUTES TO BONE CANCER PAIN IN RATS. BONE CANCER PAIN (BCP) IS EXCRUCIATING FOR CANCER PATIENTS, WITH LIMITED CLINICAL TREATMENT OPTIONS AND SIGNIFICANT SIDE EFFECTS, DUE TO THE COMPLEX AND UNCLEAR PATHOGENESIS OF BONE CANCER PAIN. PERIPHERAL SENSITIZATION IN DORSAL ROOT GANGLION (DRG) NEURONS IS A RECOGNIZED CELLULAR MECHANISM FOR BONE CANCER PAIN. THE PATHOLOGICAL MECHANISM OF CHRONIC PAIN IS INCREASINGLY BEING AFFECTED BY EPIGENETIC MECHANISMS. IN THIS STUDY, WE UNBIASEDLY SHOWED THAT THE DNA HYDROXYMETHYLASE TEN-ELEVEN TRANSLOCATION 1 (TET1) EXPRESSION WAS SIGNIFICANTLY INCREASED IN THE L4-6 DRG OF BCP RATS AND TEN-ELEVEN TRANSLOCATION 2 (TET2) EXPRESSION DID NOT CHANGE SIGNIFICANTLY. NOTABLY, TET1 INHIBITION BY INTRATHECAL INJECTION OF BOBCAT339 (A TET1 INHIBITOR) EFFECTIVELY RELIEVED MECHANICAL HYPERALGESIA IN BCP RATS. PERIPHERAL SENSITIZATION IN CHRONIC PAIN RELIES ON THE ACTIVATION AND OVEREXPRESSION OF ION CHANNELS ON NEURONS. HERE, WE DEMONSTRATED THAT TRPV4, ONE OF THE TRANSIENT RECEPTOR POTENTIAL ION CHANNEL FAMILY MEMBERS, WAS SIGNIFICANTLY ELEVATED IN THE L4-6 DRG OF BCP RATS. IN ADDITION, TRPV4 INHIBITION BY INTRATHECAL INJECTION OF HC067047 (A TRPV4 INHIBITOR) ALSO SIGNIFICANTLY ATTENUATED MECHANICAL HYPERALGESIA IN BCP RATS. INTERESTINGLY, WE FOUND THAT TET1 INHIBITION DOWNREGULATED TRPV4 EXPRESSION IN THE L4-6 DRG OF BCP RATS. AS A RESULT, THESE FINDINGS SUGGESTED THAT TET1 MAY CONTRIBUTE TO BONE CANCER PAIN BY UPREGULATING TRPV4 EXPRESSION IN THE L4-6 DRG OF BCP RATS AND THAT TET1 OR TRPV4 MAY BECOME THERAPEUTIC TARGETS FOR BONE CANCER PAIN. 2023 4 2052 27 EPIGENETIC CONNECTION OF THE CALCITONIN GENE-RELATED PEPTIDE AND ITS POTENTIAL IN MIGRAINE. THE CALCITONIN GENE-RELATED PEPTIDE (CGRP) IS IMPLICATED IN THE PATHOGENESIS OF SEVERAL PAIN-RELATED SYNDROMES, INCLUDING MIGRAINE. TARGETING CGRP AND ITS RECEPTOR BY THEIR ANTAGONISTS AND ANTIBODIES WAS A BREAKTHROUGH IN MIGRAINE THERAPY, BUT THE NEED TO IMPROVE EFFICACY AND LIMIT THE SIDE EFFECTS OF THESE DRUGS JUSTIFY FURTHER STUDIES ON THE REGULATION OF CGRP IN MIGRAINE. THE EXPRESSION OF THE CGRP ENCODING GENE, CALCA, IS MODULATED BY EPIGENETIC MODIFICATIONS, INCLUDING THE DNA METHYLATION, HISTONE MODIFICATION, AND EFFECTS OF MICRO RNAS (MIRNAS), CIRCULAR RNAS, AND LONG-CODING RNAS (LNCRNAS). ON THE OTHER HAND, CGRP CAN CHANGE THE EPIGENETIC PROFILE OF NEURONAL AND GLIAL CELLS. THE PROMOTER OF THE CALCA GENE HAS TWO CPG ISLANDS THAT MAY BE SPECIFICALLY METHYLATED IN MIGRAINE PATIENTS. DNA METHYLATION AND LNCRNAS WERE SHOWN TO PLAY A ROLE IN THE CELL-SPECIFIC ALTERNATIVE SPLICING OF THE CALCA PRIMARY TRANSCRIPT. CGRP MAY BE INVOLVED IN CHANGES IN NEURAL CYTOARCHITECTURE THAT ARE CONTROLLED BY HISTONE DEACETYLASE 6 (HDAC6) AND CAN BE RELATED TO MIGRAINE. INHIBITION OF HDAC6 RESULTS IN REDUCED CORTICAL-SPREADING DEPRESSION AND A BLOCKADE OF THE CGRP RECEPTOR. CGRP LEVELS ARE ASSOCIATED WITH THE EXPRESSION OF SEVERAL MIRNAS IN PLASMA, MAKING THEM USEFUL PERIPHERAL MARKERS OF MIGRAINE. THE FUNDAMENTAL ROLE OF CGRP IN INFLAMMATORY PAIN TRANSMISSION MAY BE EPIGENETICALLY REGULATED. IN CONCLUSION, EPIGENETIC CONNECTIONS OF CGRP SHOULD BE FURTHER EXPLORED FOR EFFICIENT AND SAFE ANTIMIGRAINE THERAPY. 2022 5 4616 31 NERVE INJURY INCREASES BRAIN-DERIVED NEUROTROPHIC FACTOR LEVELS TO SUPPRESS BK CHANNEL ACTIVITY IN PRIMARY SENSORY NEURONS. ABNORMAL HYPEREXCITABILITY OF PRIMARY SENSORY NEURONS CONTRIBUTES TO NEUROPATHIC PAIN DEVELOPMENT AFTER NERVE INJURY. NERVE INJURY PROFOUNDLY REDUCES THE EXPRESSION OF BIG CONDUCTANCE CA(2+) -ACTIVATED K(+) (BK) CHANNELS IN THE DORSAL ROOT GANGLION (DRG). HOWEVER, LITTLE IS KNOWN ABOUT HOW NERVE INJURY AFFECTS BK CHANNEL ACTIVITY IN DRG NEURONS. IN THIS STUDY, WE DETERMINED THE CHANGES IN BK CHANNEL ACTIVITY IN DRG NEURONS IN A RAT MODEL OF NEUROPATHIC PAIN AND THE CONTRIBUTION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) TO REDUCED BK CHANNEL ACTIVITY. THE BK CHANNEL ACTIVITY WAS PRESENT PREDOMINANTLY IN SMALL AND MEDIUM DRG NEURONS, AND LIGATION OF L5 AND L6 SPINAL NERVES PROFOUNDLY DECREASED THE BK CURRENT DENSITY IN THESE NEURONS. BLOCKING BK CHANNELS SIGNIFICANTLY INCREASED NEURONAL EXCITABILITY IN SHAM CONTROL, BUT NOT IN NERVE-INJURED, RATS. THE BDNF CONCENTRATION IN THE DRG WAS SIGNIFICANTLY GREATER IN NERVE-INJURED RATS THAN IN CONTROL RATS. BDNF TREATMENT LARGELY REDUCED BK CURRENTS IN DRG NEURONS IN CONTROL RATS, WHICH WAS BLOCKED BY EITHER ANTI-BDNF ANTIBODY OR K252A, A TRK RECEPTOR INHIBITOR. FURTHERMORE, EITHER ANTI-BDNF ANTIBODY OR K252A REVERSED REDUCTION IN BK CURRENTS IN INJURED DRG NEURONS. BDNF TREATMENT REDUCED THE MRNA LEVELS OF BKALPHA1 SUBUNIT IN DRG NEURONS, AND ANTI-BDNF ANTIBODY ATTENUATED THE REDUCTION IN THE BKALPHA1 MRNA LEVEL IN INJURED DRG NEURONS. THESE FINDINGS SUGGEST THAT NERVE INJURY PRIMARILY DIMINISHES THE BK CHANNEL ACTIVITY IN SMALL AND MEDIUM DRG NEURONS. INCREASED BDNF LEVELS CONTRIBUTE TO REDUCED BK CHANNEL ACTIVITY IN DRG NEURONS THROUGH EPIGENETIC AND TRANSCRIPTIONAL MECHANISMS IN NEUROPATHIC PAIN. 2012 6 2452 29 EPIGENETIC SUPPRESSION OF POTASSIUM-CHLORIDE CO-TRANSPORTER 2 EXPRESSION IN INFLAMMATORY PAIN INDUCED BY COMPLETE FREUND'S ADJUVANT (CFA). BACKGROUND: MULTIPLE MECHANISMS CONTRIBUTE TO THE STIMULUS-EVOKED PAIN HYPERSENSITIVITY THAT MAY BE EXPERIENCED AFTER PERIPHERAL INFLAMMATION. PERSISTENT PATHOLOGICAL STIMULI IN MANY PAIN CONDITIONS AFFECT THE EXPRESSION OF CERTAIN GENES THROUGH EPIGENETIC ALTERNATIONS. THE MAIN PURPOSE OF OUR STUDY WAS TO INVESTIGATE THE ROLE OF EPIGENETIC MODIFICATION ON POTASSIUM-CHLORIDE CO-TRANSPORTER 2 (KCC2) GENE EXPRESSION IN THE PERSISTENCE OF INFLAMMATORY PAIN. METHODS: PERSISTENT INFLAMMATORY PAIN WAS INDUCED THROUGH THE INJECTION OF COMPLETE FREUND'S ADJUVANT (CFA) IN THE LEFT HIND PAW OF RATS. ACETYL-HISTONE H3 AND H4 LEVEL WAS DETERMINED BY CHROMATIN IMMUNOPRECIPITATION IN THE SPINAL DORSAL HORN. PAIN BEHAVIOUR AND INHIBITORY SYNAPTIC FUNCTION OF SPINAL CORD WERE DETERMINED BEFORE AND AFTER CFA INJECTION. KCC2 EXPRESSION WAS DETERMINED BY REAL TIME RT-PCR AND WESTERN BLOT. INTRATHECAL KCC2 SIRNA (2 MUG PER 10 MUL PER RAT) OR HDAC INHIBITOR (10 MUG PER 10 MUL PER RAT) WAS INJECTED ONCE DAILY FOR 3 DAYS BEFORE CFA INJECTION. RESULTS: PERSISTENT INFLAMMATORY PAIN EPIGENETICALLY SUPPRESSED KCC2 EXPRESSION THROUGH HISTONE DEACETYLASE (HDAC)-MEDIATED HISTONE HYPOACETYLATION, RESULTING IN DECREASED INHIBITORY SIGNALLING EFFICACY. KCC2 KNOCK-DOWN CAUSED BY INTRATHECAL ADMINISTRATION OF KCC2 SIRNA IN NAIVE RATS REDUCED KCC2 EXPRESSION IN THE SPINAL CORD, LEADING TO SENSITIZED PAIN BEHAVIOURS AND IMPAIRED INHIBITORY SYNAPTIC TRANSMISSION IN THEIR SPINAL CORDS. MOREOVER, INTRATHECAL HDAC INHIBITOR INJECTION IN CFA RATS INCREASED KCC2 EXPRESSION, PARTIALLY RESTORING THE SPINAL INHIBITORY SYNAPTIC TRANSMISSION AND RELIEVING THE SENSITIZED PAIN BEHAVIOUR. CONCLUSION: THESE FINDINGS SUGGEST THAT THE TRANSCRIPTION OF SPINAL KCC2 IS REGULATED BY HISTONE ACETYLATION EPIGENETICALLY FOLLOWING CFA. SIGNIFICANCE: PERSISTENT PAIN SUPPRESSES KCC2 EXPRESSION THROUGH HDAC-MEDIATED HISTONE HYPOACETYLATION AND CONSEQUENTLY IMPAIRS THE INHIBITORY FUNCTION OF INHIBITORY INTERNEURONS. DRUGS SUCH AS HDAC INHIBITORS THAT SUPPRESS THE INFLUENCES OF PERSISTENT PAIN ON THE EXPRESSION OF KCC2 MAY SERVE AS A NOVEL ANALGESIC. 2017 7 6536 29 TRANSCRIPTIONAL REGULATION OF TYPE-2 METABOTROPIC GLUTAMATE RECEPTORS: AN EPIGENETIC PATH TO NOVEL TREATMENTS FOR CHRONIC PAIN. ACTIVATION OF METABOTROPIC GLUTAMATE 2 (MGLU2) RECEPTORS INHIBITS PAIN TRANSMISSION AT THE SYNAPSES BETWEEN PRIMARY AFFERENT FIBERS AND NEURONS IN THE DORSAL HORN OF THE SPINAL CORD. IN ADDITION, MGLU2 RECEPTORS ARE FOUND IN PERIPHERAL NOCICEPTORS, AND IN PAIN-REGULATORY CENTERS OF THE BRAIN STEM AND FOREBRAIN. MGLU2 RECEPTOR AGONISTS PRODUCE ANALGESIA IN MODELS OF INFLAMMATORY AND NEUROPATHIC PAIN, BUT THEIR USE IS LIMITED BY THE DEVELOPMENT OF TOLERANCE. A NEW THERAPEUTIC STRATEGY COULD BE BASED ON THE TRANSCRIPTIONAL REGULATION OF MGLU2 RECEPTORS VIA THE ACETYLATION-PROMOTED ACTIVATION OF THE P65/RELA TRANSCRIPTION FACTOR. "EPIGENETIC" DRUGS THAT INCREASE MGLU2 RECEPTOR EXPRESSION, INCLUDING L-ACETYLCARNITINE AND INHIBITORS OF HISTONE DEACETYLASES, HAVE A DIFFERENT ANALGESIC PROFILE WITH NO TOLERANCE TO THE THERAPEUTIC EFFECT AFTER REPEATED DOSING. 2010 8 2751 33 EXPRESSION OF ACETYL-HISTONE H3 AND ACETYL-HISTONE H4 IN DORSAL ROOT GANGLION AND SPINAL DORSAL HORN IN RAT CHRONIC PAIN MODELS. AIMS: HISTONE ACETYLATION AND DEACETYLATION ARE TWO HISTONE POSTTRANSLATIONAL MODIFICATIONS THAT ARE USUALLY CONTROLLED BY HISTONE ACETYLTRANSFERASES (HATS) AND HISTONE DEACETYLASES (HDACS). ALTHOUGH HATS OR HDACS INHIBITORS COULD RELIEVE PAIN HYPERSENSITIVITIES IN CHRONIC PAIN ANIMAL MODELS, IT IS NOT CLEAR ON THE EXPRESSION OF GLOBAL HISTONE ACETYLATION IN THE DORSAL ROOT GANGLION (DRG) OR SPINAL DORSAL HORN IN CHRONIC PAIN CONDITIONS. MAIN METHODS: A SPINAL NERVE LIGATION (SNL)-INDUCED NEUROPATHIC PAIN MODEL AND A COMPLETE FREUND'S ADJUVANT (CFA)-INDUCED INFLAMMATORY PAIN MODEL IN RATS WERE USED TO EXAMINE THE EXPRESSION OF TOTAL ACETYL-HISTONE H3 (ACH3) AND TOTAL ACETYL-HISTONE H4 (ACH4) BY IMMUNOFLUORESCENCE OR WESTERN BLOT. KEY FINDINGS: ACH3 AND ACH4 NOT ONLY LOCALIZED IN NEURONAL NUCLEI, BUT ALSO IN NUCLEI OF GLIAL CELLS IN THE DRG. UNILATERAL SNL INDUCED THE INCREASE OF ACH3 AND ACH4 EXPRESSION IN THE INJURED LUMBAR 5 (L5) DRG, BUT NOT IN THE UNINJURED L5 DRG OR THE SPINAL DORSAL HORN, WHILE UNILATERAL INTRAPLANTAR INJECTION OF CFA INCREASED ACH3 AND ACH4 EXPRESSION IN THE IPSILATERAL L4/5 SPINAL DORSAL HORN, BUT NOT IN THE L4/5 DRG. SIGNIFICANCE: THESE RESULTS PROVIDE MORPHOLOGICAL EVIDENCE FOR GLOBAL HISTONE ACETYLATION EXPRESSION IN THE DRG AND SPINAL CORD AND INDICATE THE DIFFERENTIAL EXPRESSION IN THE DRG AND SPINAL DORSAL HORN IN DIFFERENT CHRONIC PAIN MODELS. MORE PRECISE EPIGENETIC MECHANISMS OF HISTONE ACETYLATION ON THE TARGET GENES NEED TO BE REVEALED. 2018 9 4172 31 MELATONIN IMPEDES TET1-DEPENDENT MGLUR5 PROMOTER DEMETHYLATION TO RELIEVE PAIN. MELATONIN (N-ACETYL-5-METHOXYTRYPTAMINE)/MT2 RECEPTOR-DEPENDENT EPIGENETIC MODIFICATION REPRESENTS A NOVEL PATHWAY IN THE TREATMENT OF NEUROPATHIC PAIN. BECAUSE SPINAL TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE 1 (TET1)-DEPENDENT EPIGENETIC DEMETHYLATION HAS RECENTLY BEEN LINKED TO PAIN HYPERSENSITIVITY, WE HYPOTHESIZED THAT MELATONIN/MT2-DEPENDENT ANALGESIA INVOLVES SPINAL TET1-DEPENDENT DEMETHYLATION. HERE, WE SHOWED THAT SPINAL TET1 GENE TRANSFER BY INTRATHECAL DELIVERY OF TET1-ENCODING VECTORS TO NAIVE RATS PRODUCED PROFOUND AND LONG-LASTING NOCICEPTIVE HYPERSENSITIVITY. IN ADDITION, ENHANCED TET1 EXPRESSION, TET1-METABOTROPIC GLUTAMATE RECEPTOR SUBTYPE 5 (MGLUR5) PROMOTER COUPLING, DEMETHYLATION AT THE MGLUR5 PROMOTER, AND MGLUR5 EXPRESSION IN DORSAL HORN NEURONS WERE OBSERVED. RATS SUBJECTED TO SPINAL NERVE LIGATION AND INTRAPLANTAR COMPLETE FREUND'S ADJUVANT INJECTION DISPLAYED TACTILE ALLODYNIA AND BEHAVIORAL HYPERALGESIA ASSOCIATED WITH SIMILAR CHANGES IN THE DORSAL HORN. NOTABLY, INTRATHECAL MELATONIN INJECTION REVERSED THE PROTEIN EXPRESSION, PROTEIN-PROMOTER COUPLING, PROMOTER DEMETHYLATION, AND PAIN HYPERSENSITIVITY INDUCED BY TET1 GENE TRANSFER, SPINAL NERVE LIGATION, AND INTRAPLANTAR COMPLETE FREUND'S ADJUVANT INJECTION. ALL THE EFFECTS CAUSED BY MELATONIN WERE BLOCKED BY PRETREATMENT WITH A MT2 RECEPTOR-SELECTIVE ANTAGONIST. IN CONCLUSION, MELATONIN RELIEVES PAIN BY IMPEDING TET1-DEPENDENT DEMETHYLATION OF MGLUR5 IN DORSAL HORN NEURONS THROUGH THE MT2 RECEPTOR. OUR FINDINGS LINK MELATONIN/MT2 SIGNALING TO TET1-DEPENDENT EPIGENETIC DEMETHYLATION OF NOCICEPTIVE GENES FOR THE FIRST TIME AND SUGGEST MELATONIN AS A PROMISING THERAPY FOR THE TREATMENT OF PAIN. 2017 10 3191 37 HDAC AND HAT INHIBITORS DIFFERENTLY AFFECT ANALGESIA MEDIATED BY GROUP II METABOTROPIC GLUTAMATE RECEPTORS. BACKGROUND: HISTONE DEACETYLASES (HDACS) AND HISTONE ACETYLTRANSFERASES (HATS) ARE KEY PLAYERS IN EPIGENETIC REGULATION OF GENE EXPRESSION. ANALGESIC ACTIVITY BY HDAC INHIBITORS HAS BEEN REPORTED IN DIFFERENT PAIN MODELS INCLUDING INFLAMMATORY AND NEUROPATHIC PAIN. THESE DRUGS INTERFERE WITH GENE EXPRESSION THROUGH DIFFERENT MECHANISMS INCLUDING CHROMATIN REMODELING AND/OR ACTIVATION OF TRANSCRIPTION FACTORS. AMONG OTHER TARGETS, HDAC INHIBITORS REGULATE METABOTROPIC GLUTAMATE RECEPTORS TYPE 2 (MGLU2) EXPRESSION IN CENTRAL AND PERIPHERAL CENTRAL NERVOUS SYSTEM. HOWEVER WHETHER INHIBITION OF HAT ACTIVITY ALSO REGULATES MGLU2 EXPRESSION HAS NOT BEEN REPORTED. FINDINGS: HERE WE REPORT THAT CURCUMIN (CUR), A NATURALLY OCCURRING COMPOUND ENDOWED WITH P300/CREB-BINDING PROTEIN HAT INHIBITORY ACTIVITY, IS ABLE TO INDUCE A DRASTIC DOWN-REGULATION OF THE MGLU2 RECEPTOR IN THE MOUSE SPINAL CORD AFTER SYSTEMIC ADMINISTRATION TOGETHER WITH A MARKED HYPOACETYLATION OF HISTONES H3 AND H4 IN DORSAL ROOT GANGLIA (DRG). FURTHERMORE, THE ANALGESIC ACTIVITY OF THE MGLU2/3 AGONIST, LY379268 IS LOST AFTER A 3-DAY TREATMENT WITH CUR. CONVERSELY THE ANALGESIC ACTIVITY OF LY379268 IS POTENTIATED IN MICE PRETREATED FOR 5 CONSECUTIVE DAYS WITH THE HDAC INHIBITOR, SUBEROYLANILIDE HYDROXAMIC ACID (SAHA), KNOWN TO INDUCE MGLU2-UPREGULATION. CONCLUSIONS: OUR RESULTS DEMONSTRATE THAT SYSTEMICALLY INJECTED CUR IS ABLE TO INHIBIT H3 AND H4 ACETYLATION IN THE DRG AND TO DOWN-REGULATE MGLU2 RECEPTORS IN THE SPINAL CORD. WE ALSO DEMONSTRATE THAT LONG TERM MODIFICATION OF THE MGLU2 EXPRESSION AFFECTS THE ANALGESIC PROPERTIES OF THE ORTHOSTERIC MGLU2/3 AGONIST, LY379268. THESE DATA OPEN UP THE POSSIBILITY THAT EPIGENETIC MODULATORS MIGHT BE GIVEN IN COMBINATION WITH "TRADITIONAL" DRUGS IN A CONTEXT OF A MULTI TARGET APPROACH FOR A BETTER ANALGESIC EFFICACY. 2014 11 3721 38 INHIBITION OF CLASS II HISTONE DEACETYLASES IN THE SPINAL CORD ATTENUATES INFLAMMATORY HYPERALGESIA. BACKGROUND: SEVERAL CLASSES OF HISTONE DEACETYLASES (HDACS) ARE EXPRESSED IN THE SPINAL CORD THAT IS A CRITICAL STRUCTURE OF THE NOCICEPTIVE PATHWAY. HDAC-REGULATED HISTONE ACETYLATION IS AN IMPORTANT COMPONENT OF CHROMATIN REMODELING LEADING TO EPIGENETIC REGULATION OF GENE TRANSCRIPTION. TO UNDERSTAND THE ROLE OF HISTONE ACETYLATION IN EPIGENETIC REGULATION OF PATHOLOGICAL PAIN, WE HAVE STUDIED THE IMPACT OF DIFFERENT CLASSES OF HDACS IN THE SPINAL CORD ON INFLAMMATORY HYPERALGESIA INDUCED BY COMPLETE FREUND'S ADJUVANT (CFA). RESULTS: WE INTRATHECALLY APPLIED INHIBITORS SPECIFIC TO DIFFERENT CLASSES OF HDACS AND EVALUATED THEIR IMPACT ON INFLAMMATORY HYPERALGESIA. PRE-INJECTED INHIBITORS TARGETING CLASS I AS WELL AS II (SAHA, TSA, LAQ824) OR IIA (VPA, 4-PB) HDACS SIGNIFICANTLY DELAYED THE THERMAL HYPERALGESIA INDUCED BY UNILATERAL CFA INJECTION IN THE HINDPAW. EXISTING HYPERALGESIA INDUCED BY CFA WAS ALSO ATTENUATED BY THE HDAC INHIBITORS (HDACIS). IN CONTRAST, THESE INHIBITORS DID NOT INTERFERE WITH THE THERMAL RESPONSE EITHER IN NAIVE ANIMALS, OR ON THE CONTRALATERAL SIDE OF INFLAMED ANIMALS. INTERESTINGLY, MS-275 THAT SPECIFICALLY INHIBITS CLASS I HDACS FAILED TO ALTER THE HYPERALGESIA ALTHOUGH IT INCREASED HISTONE 3 ACETYLATION IN THE SPINAL CORD AS SAHA DID. USING IMMUNOBLOT ANALYSIS, WE FURTHER FOUND THAT THE LEVELS OF CLASS IIA HDAC MEMBERS (HDAC4, 5, 7, 9) IN THE SPINAL DORSAL HORN WERE UPREGULATED FOLLOWING CFA INJECTION WHILE THOSE OF CLASS I HDAC MEMBERS (HDAC1, 2, 3) REMAINED STABLE OR WERE SLIGHTLY REDUCED. CONCLUSIONS: OUR DATA SUGGEST THAT ACTIVITY OF CLASS II HDACS IN THE SPINAL CORD IS CRITICAL TO THE INDUCTION AND MAINTENANCE OF INFLAMMATORY HYPERALGESIA INDUCED BY CFA, WHILE ACTIVITY OF CLASS I HDACS MAY BE UNNECESSARY. COMPARISON OF THE EFFECTS OF HDACIS SPECIFIC TO CLASS II AND IIA AS WELL AS THE EXPRESSION PATTERN OF DIFFERENT HDACS IN THE SPINAL CORD IN RESPONSE TO CFA SUGGESTS THAT THE MEMBERS OF CLASS IIA HDACS MAY BE POTENTIAL TARGETS FOR ATTENUATING PERSISTENT INFLAMMATORY PAIN. 2010 12 1120 42 COMPARISON OF DIFFERENT HISTONE DEACETYLASE INHIBITORS IN ATTENUATING INFLAMMATORY PAIN IN RATS. HISTONE DEACETYLASE INHIBITORS (HDACIS), WHICH INTERFERE WITH THE EPIGENETIC PROCESS OF HISTONE ACETYLATION, HAVE SHOWN ANALGESIC EFFECTS IN ANIMAL MODELS OF PERSISTENT PAIN. THE HDAC FAMILY COMPRISES 18 GENES; HOWEVER, THE DIFFERENT EFFECTS OF DISTINCT CLASSES OF HDACIS ON PAIN RELIEF REMAIN UNCLEAR. THE AIM OF THIS STUDY WAS TO DETERMINE THE EFFICACY OF THESE HDACIS ON ATTENUATING THERMAL HYPERALGESIA IN PERSISTENT INFLAMMATORY PAIN. PERSISTENT INFLAMMATORY PAIN WAS INDUCED BY INJECTING COMPLETE FREUND'S ADJUVANT (CFA) INTO THE LEFT HIND PAW OF RATS. THEN, HDACIS TARGETING CLASS I (ENTINOSTAT (MS-275)) AND CLASS IIA (SODIUM BUTYRATE, VALPROIC ACID (VPA), AND 4-PHENYLBUTYRIC ACID (4-PBA)), OR CLASS II (SUBEROYLANILIDE HYDOXAMIC ACID (SAHA), TRICHOSTATIN A (TSA), AND DACINOSTAT (LAQ824)) WERE ADMINISTERED INTRAPERITONEALLY ONCE DAILY FOR 3 OR 4 DAYS. WE FOUND THAT THE INJECTION OF SAHA ONCE A DAY FOR 3 DAYS SIGNIFICANTLY ATTENUATED CFA-INDUCED THERMAL HYPERALGESIA FROM DAY 4 AND LASTED 7 DAYS. IN COMPARISON WITH SAHA, SUPPRESSION OF HYPERALGESIA BY 4-PBA PEAKED ON DAY 2, WHEREAS THAT BY MS-275 OCCURRED ON DAYS 5 AND 6. FATIGUE WAS A SERIOUS SIDE EFFECT SEEN WITH MS-275. THESE FINDINGS WILL BE BENEFICIAL FOR OPTIMIZING THE SELECTION OF SPECIFIC HDACIS IN MEDICAL FIELDS SUCH AS PAIN MEDICINE AND NEUROPSYCHIATRY. 2019 13 3869 28 JNK1 REGULATES HISTONE ACETYLATION IN TRIGEMINAL NEURONS FOLLOWING CHEMICAL STIMULATION. TRIGEMINAL NERVE FIBERS IN NASAL AND ORAL CAVITIES ARE SENSITIVE TO VARIOUS ENVIRONMENTAL HAZARDOUS STIMULI, WHICH TRIGGER MANY NEUROTOXIC PROBLEMS SUCH AS CHRONIC MIGRAINE HEADACHE AND TRIGEMINAL IRRITATED DISORDERS. HOWEVER, THE ROLE OF JNK KINASE CASCADE AND ITS EPIGENETIC MODULATION OF HISTONE REMODELING IN TRIGEMINAL GANGLION (TG) NEURONS ACTIVATED BY ENVIRONMENTAL NEUROTOXINS REMAINS UNKNOWN. HERE WE INVESTIGATED THE ROLE OF JNK/C-JUN CASCADE IN THE REGULATION OF ACETYLATION OF H3 HISTONE IN TG NEURONS FOLLOWING IN VITRO STIMULATION BY A NEURO-INFLAMMATORY AGENT, MUSTARD OIL (MO). WE FOUND THAT MO STIMULATION ELICITED JNK/C-JUN PATHWAY SIGNIFICANTLY BY ENHANCING PHOSPHO-JNK1, PHOSPHO-C-JUN EXPRESSION, AND C-JUN ACTIVITY, WHICH WERE CORRELATED WITH AN ELEVATED ACETYLATED H3 HISTONE IN TG NEURONS. HOWEVER, INCREASES IN PHOSPHO-C-JUN AND C-JUN ACTIVITY WERE SIGNIFICANTLY BLOCKED BY A JNK INHIBITOR, SP600125. WE ALSO FOUND THAT ALTERED H3 HISTONE REMODELING, ASSESSED BY H3 ACETYLATION IN TRIGGERED TG NEURONS, WAS REDUCED BY SP600125. THE STUDY SUGGESTS THAT THE ACTIVATED JNK SIGNALING IN REGULATION OF HISTONE REMODELING MAY CONTRIBUTE TO NEURO-EPIGENTIC CHANGES IN PERIPHERAL SENSORY NEURONS FOLLOWING ENVIRONMENTAL NEUROTOXIC EXPOSURE. 2008 14 2066 29 EPIGENETIC CONTROL OF ION CHANNEL EXPRESSION AND CELL-SPECIFIC SPLICING IN NOCICEPTORS: CHRONIC PAIN MECHANISMS AND POTENTIAL THERAPEUTIC TARGETS. ION CHANNELS UNDERLIE ALL FORMS FOR ELECTRICAL SIGNALING INCLUDING THE TRANSMISSION OF INFORMATION ABOUT HARMFUL EVENTS. VOLTAGE-GATED CALCIUM ION CHANNELS HAVE DUAL FUNCTION, THEY SUPPORT ELECTRICAL SIGNALING AS WELL AS INTRACELLULAR CALCIUM SIGNALING THROUGH EXCITATION-DEPENDENT CALCIUM ENTRY ACROSS THE PLASMA MEMBRANE. MECHANISMS THAT REGULATE ION CHANNEL FORMS AND ACTIONS ARE ESSENTIAL FOR MYRIAD CELL FUNCTIONS AND THESE ARE TARGETED BY DRUGS AND THERAPEUTICS. WHEN DISRUPTED, THE CELLULAR MECHANISMS THAT CONTROL ION CHANNEL ACTIVITY CAN CONTRIBUTE TO DISEASE PATHOPHYSIOLOGY. FOR EXAMPLE, ALTERNATIVE PRE-MRNA SPLICING IS A MAJOR STEP IN DEFINING THE PRECISE COMPOSITION OF THE TRANSCRIPTOME ACROSS DIFFERENT CELL TYPES FROM EARLY CELLULAR DIFFERENTIATION TO PROGRAMMED APOPTOSIS. AN ESTIMATED 30% OF DISEASE-CAUSING MUTATIONS ARE ASSOCIATED WITH ALTERED ALTERNATIVE SPLICING, AND MIS-SPLICING IS A FEATURE OF NUMEROUS HIGHLY PREVALENT DISEASES INCLUDING NEURODEGENERATIVE, CANCER, AND CHRONIC PAIN. HERE WE DISCUSS THE IMPORTANT ROLE OF EPIGENETIC REGULATION OF GENE EXPRESSION AND CELL-SPECIFIC ALTERNATIVE SPLICING OF CALCIUM ION CHANNELS IN NOCICEPTORS, WITH EMPHASIS ON HOW THESE PROCESSES ARE DISRUPTED IN CHRONIC PAIN, THE POTENTIAL THERAPEUTIC BENEFIT OF CORRECTING OR COMPENSATING FOR ABERRANT ION CHANNEL SPLICING IN CHRONIC PAIN. 2021 15 5155 29 PRDM12 MODULATES PAIN-RELATED BEHAVIOR BY REMODELING GENE EXPRESSION IN MATURE NOCICEPTORS. PRDM12 IS A CONSERVED EPIGENETIC TRANSCRIPTIONAL REGULATOR THAT DISPLAYS RESTRICTED EXPRESSION IN NOCICEPTORS OF THE DEVELOPING PERIPHERAL NERVOUS SYSTEM. IN MICE, PRDM12 IS REQUIRED FOR THE DEVELOPMENT OF THE ENTIRE NOCICEPTIVE LINEAGE. IN HUMANS, PRDM12 MUTATIONS CAUSE CONGENITAL INSENSITIVITY TO PAIN, LIKELY BECAUSE OF THE LOSS OF NOCICEPTORS. PRDM12 EXPRESSION IS MAINTAINED IN MATURE NOCICEPTORS SUGGESTING A YET-TO-BE EXPLORED FUNCTIONAL ROLE IN ADULTS. USING PRDM12 INDUCIBLE CONDITIONAL KNOCKOUT MOUSE MODELS, WE REPORT THAT IN ADULT NOCICEPTORS PRDM12 IS NO LONGER REQUIRED FOR CELL SURVIVAL BUT CONTINUES TO PLAY A ROLE IN THE TRANSCRIPTIONAL CONTROL OF A NETWORK OF GENES, MANY OF THEM ENCODING ION CHANNELS AND RECEPTORS. WE FOUND THAT DISRUPTION OF PRDM12 ALTERS THE EXCITABILITY OF DORSAL ROOT GANGLION NEURONS IN CULTURE. PHENOTYPICALLY, WE OBSERVED THAT MICE LACKING PRDM12 EXHIBIT NORMAL RESPONSES TO THERMAL AND MECHANICAL NOCICEPTIVE STIMULI BUT A REDUCED RESPONSE TO CAPSAICIN AND HYPERSENSITIVITY TO FORMALIN-INDUCED INFLAMMATORY PAIN. TOGETHER, OUR DATA INDICATE THAT PRDM12 REGULATES PAIN-RELATED BEHAVIOR IN A COMPLEX WAY BY MODULATING GENE EXPRESSION IN ADULT NOCICEPTORS AND CONTROLLING THEIR EXCITABILITY. THE RESULTS ENCOURAGE FURTHER STUDIES TO ASSESS THE POTENTIAL OF PRDM12 AS A TARGET FOR ANALGESIC DEVELOPMENT. 2022 16 687 32 BRAINSTEM BRAIN-DERIVED NEUROTROPHIC FACTOR SIGNALING IS REQUIRED FOR HISTONE DEACETYLASE INHIBITOR-INDUCED PAIN RELIEF. OUR PREVIOUS STUDY DEMONSTRATED THAT PERSISTENT PAIN CAN EPIGENETICALLY SUPPRESS THE TRANSCRIPTION OF GAD2 [ENCODING GLUTAMIC ACID DECARBOXYLASE 65 (GAD65)] AND CONSEQUENTLY IMPAIR THE INHIBITORY FUNCTION OF GABAERGIC SYNAPSES IN CENTRAL PAIN-MODULATING NEURONS. THIS CONTRIBUTES TO THE DEVELOPMENT OF PERSISTENT PAIN SENSITIZATION. HISTONE DEACETYLASE (HDAC) INHIBITORS INCREASED GAD65 ACTIVITY CONSIDERABLY, RESTORED GABA SYNAPTIC FUNCTION, AND RENDERED SENSITIZED PAIN BEHAVIOR LESS PRONOUNCED. HOWEVER, THE MOLECULAR MECHANISMS BY WHICH HDAC REGULATES GABAERGIC TRANSMISSION THROUGH GAD65 UNDER PAIN CONDITIONS ARE UNKNOWN. THIS WORK SHOWED THAT HDAC INHIBITOR-INDUCED INCREASES IN COLOCALIZATION OF GAD65 AND SYNAPTIC PROTEIN SYNAPSIN I ON THE PRESYNAPTIC AXON TERMINALS OF THE NUCLEUS RAPHE MAGNUS (NRM) WERE BLOCKED BY A TRKB RECEPTOR ANTAGONIST K252A [(9S,10R,12R)-2,3,9,10,11,12-HEXAHYDRO-10-HYDROXY-9-METHYL-1-OXO-9,12-EPOXY-1H-DIINDOLO[1,2,3-FG:3',2',1'-KL]PYRROLO[3,4-I][1,6]BENZODIAZOCINE-10-CARBOXYLIC ACID METHYL ESTER], INDICATING THAT BDNF-TRKB SIGNALING MAY BE REQUIRED IN GAD65 MODULATION OF GABA SYNAPTIC FUNCTION. AT THE BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) PROMOTER, HDAC INHIBITORS INDUCED SIGNIFICANT INCREASES IN H3 HYPERACETYLATION, CONSISTENT WITH THE INCREASE IN BDNF MRNA AND TOTAL PROTEINS. ALTHOUGH EXOGENOUS BDNF FACILITATED GABA MINIATURE INHIBITORY POSTSYNAPTIC CURRENTS AND GAD65 ACCUMULATION IN NRM NEURONAL SYNAPSES IN NORMAL RATS, IT FAILED TO DO SO IN ANIMALS SUBJECTED TO PERSISTENT INFLAMMATION. IN ADDITION, BLOCKADE OF THE TRKB RECEPTOR WITH K252A HAS NO EFFECT ON MINIATURE INHIBITORY POSTSYNAPTIC CURRENTS AND SYNAPTIC GAD65 ACCUMULATION UNDER NORMAL CONDITIONS. IN ADDITION, THE ANALGESIC EFFECTS OF HDAC INHIBITORS ON BEHAVIOR WERE BLOCKED BY NRM INFUSION OF K252A. THESE FINDINGS SUGGEST THAT BDNF-TRKB SIGNALING IS REQUIRED FOR DRUGS THAT REVERSE THE EPIGENETIC EFFECTS OF CHRONIC PAIN AT THE GENE LEVEL, SUCH AS HDAC INHIBITORS. 2015 17 2448 29 EPIGENETIC SUPPRESSION OF GAD65 EXPRESSION MEDIATES PERSISTENT PAIN. CHRONIC PAIN IS A COMMON NEUROLOGICAL DISEASE INVOLVING LASTING, MULTIFACETED MALADAPTATIONS RANGING FROM GENE MODULATION TO SYNAPTIC DYSFUNCTION AND EMOTIONAL DISORDERS. SUSTAINED PATHOLOGICAL STIMULI IN MANY DISEASES ALTER THE OUTPUT ACTIVITIES OF CERTAIN GENES THROUGH EPIGENETIC MODIFICATIONS, BUT IT IS UNCLEAR HOW EPIGENETIC MECHANISMS OPERATE IN THE DEVELOPMENT OF CHRONIC PAIN. WE SHOW HERE THAT IN THE RAT BRAINSTEM NUCLEUS RAPHE MAGNUS, WHICH IS IMPORTANT FOR CENTRAL MECHANISMS OF CHRONIC PAIN, PERSISTENT INFLAMMATORY AND NEUROPATHIC PAIN EPIGENETICALLY SUPPRESSES GAD2 (ENCODING GLUTAMIC ACID DECARBOXYLASE 65 (GAD65)) TRANSCRIPTION THROUGH HISTONE DEACETYLASE (HDAC)-MEDIATED HISTONE HYPOACETYLATION, RESULTING IN IMPAIRED GAMMA-AMINOBUTYRIC ACID (GABA) SYNAPTIC INHIBITION. GAD2 KNOCKOUT MICE SHOWED SENSITIZED PAIN BEHAVIOR AND IMPAIRED GABA SYNAPTIC FUNCTION IN THEIR BRAINSTEM NEURONS. IN WILD-TYPE BUT NOT GAD2 KNOCKOUT MICE, HDAC INHIBITORS STRONGLY INCREASED GAD65 ACTIVITY, RESTORED GABA SYNAPTIC FUNCTION AND RELIEVED SENSITIZED PAIN BEHAVIOR. THESE FINDINGS SUGGEST GAD65 AND HDACS AS POTENTIAL THERAPEUTIC TARGETS IN AN EPIGENETIC APPROACH TO THE TREATMENT OF CHRONIC PAIN. 2011 18 4645 28 NEUROPATHIC PAIN: FROM MECHANISMS TO TREATMENT. NEUROPATHIC PAIN CAUSED BY A LESION OR DISEASE OF THE SOMATOSENSORY NERVOUS SYSTEM IS A COMMON CHRONIC PAIN CONDITION WITH MAJOR IMPACT ON QUALITY OF LIFE. EXAMPLES INCLUDE TRIGEMINAL NEURALGIA, PAINFUL POLYNEUROPATHY, POSTHERPETIC NEURALGIA, AND CENTRAL POSTSTROKE PAIN. MOST PATIENTS COMPLAIN OF AN ONGOING OR INTERMITTENT SPONTANEOUS PAIN OF, FOR EXAMPLE, BURNING, PRICKING, SQUEEZING QUALITY, WHICH MAY BE ACCOMPANIED BY EVOKED PAIN, PARTICULAR TO LIGHT TOUCH AND COLD. ECTOPIC ACTIVITY IN, FOR EXAMPLE, NERVE-END NEUROMA, COMPRESSED NERVES OR NERVE ROOTS, DORSAL ROOT GANGLIA, AND THE THALAMUS MAY IN DIFFERENT CONDITIONS UNDERLIE THE SPONTANEOUS PAIN. EVOKED PAIN MAY SPREAD TO NEIGHBORING AREAS, AND THE UNDERLYING PATHOPHYSIOLOGY INVOLVES PERIPHERAL AND CENTRAL SENSITIZATION. MALADAPTIVE STRUCTURAL CHANGES AND A NUMBER OF CELL-CELL INTERACTIONS AND MOLECULAR SIGNALING UNDERLIE THE SENSITIZATION OF NOCICEPTIVE PATHWAYS. THESE INCLUDE ALTERATION IN ION CHANNELS, ACTIVATION OF IMMUNE CELLS, GLIAL-DERIVED MEDIATORS, AND EPIGENETIC REGULATION. THE MAJOR CLASSES OF THERAPEUTICS INCLUDE DRUGS ACTING ON ALPHA(2)DELTA SUBUNITS OF CALCIUM CHANNELS, SODIUM CHANNELS, AND DESCENDING MODULATORY INHIBITORY PATHWAYS. 2021 19 2179 25 EPIGENETIC MECHANISMS OF NEURAL PLASTICITY IN CHRONIC NEUROPATHIC PAIN. NEUROPATHIC PAIN IS A CHALLENGING CLINICAL PROBLEM AND REMAINS DIFFICULT TO TREAT. ALTERED GENE EXPRESSION IN PERIPHERAL SENSORY NERVES AND NEURONS DUE TO NERVE INJURY IS WELL DOCUMENTED AND CONTRIBUTES CRITICALLY TO THE SYNAPTIC PLASTICITY IN THE SPINAL CORD AND THE INITIATION AND MAINTENANCE OF CHRONIC PAIN. HOWEVER, OUR UNDERSTANDING OF THE EPIGENETIC MECHANISMS REGULATING THE TRANSCRIPTION OF PRO-NOCICEPTIVE (E.G., NMDA RECEPTORS AND ALPHA2DELTA-1) AND ANTINOCICEPTIVE (E.G., POTASSIUM CHANNELS AND OPIOID AND CANNABINOID RECEPTORS) GENES ARE STILL LIMITED. IN THIS REVIEW, WE SUMMARIZE RECENT STUDIES DETERMINING THE ROLES OF HISTONE MODIFICATIONS (INCLUDING METHYLATION, ACETYLATION, AND UBIQUITINATION), DNA METHYLATION, AND NONCODING RNAS IN NEUROPATHIC PAIN DEVELOPMENT. WE REVIEW THE EPIGENETIC WRITER, READER, AND ERASER PROTEINS THAT PARTICIPATE IN THE TRANSCRIPTIONAL CONTROL OF THE EXPRESSION OF KEY ION CHANNELS AND NEUROTRANSMITTER RECEPTORS IN THE DORSAL ROOT GANGLION AFTER TRAUMATIC NERVE INJURY, WHICH IS COMMONLY USED AS A PRECLINICAL MODEL OF NEUROPATHIC PAIN. A BETTER UNDERSTANDING OF EPIGENETIC REPROGRAMMING INVOLVED IN THE TRANSITION FROM ACUTE TO CHRONIC PAIN COULD LEAD TO THE DEVELOPMENT OF NEW TREATMENTS FOR NEUROPATHIC PAIN. 2022 20 3331 33 HISTONE DEACETYLASE INHIBITOR SUBERANILOHYDROXAMIC ACID TREATMENT REVERSES HYPOSENSITIVITY TO GAMMA-AMINOBUTYRIC ACID IN THE VENTRAL TEGMENTAL AREA DURING ETHANOL WITHDRAWAL. BACKGROUND: THE VENTRAL TEGMENTAL AREA (VTA) IS IMPORTANT FOR ALCOHOL-RELATED REWARD AND REINFORCEMENT. MOUSE VTA NEURONS ARE HYPOSENSITIVE TO GAMMA-AMINOBUTYRIC ACID (GABA) DURING ETHANOL (ETOH) WITHDRAWAL, AND GABA RESPONSIVENESS IS NORMALIZED BY IN VITRO TREATMENT WITH HISTONE DEACETYLASE INHIBITORS (HDACI). THE PRESENT STUDY EXAMINED THE EFFECT OF A SYSTEMICALLY ADMINISTERED HDACI, SUBERANILOHYDROXAMIC ACID (SAHA) ON GABA SENSITIVITY, AND RELATED MOLECULAR CHANGES IN VTA NEURONS DURING WITHDRAWAL AFTER CHRONIC ETOH INTAKE IN RATS. METHODS: SPRAGUE DAWLEY MALE ADULT RATS WERE FED WITH LIEBER-DECARLI DIET (9% ETOH OR CONTROL DIET) FOR 16 DAYS. EXPERIMENTAL GROUPS INCLUDED CONTROL DIET-FED AND ETOH DIET-FED (0- OR 24-HOUR WITHDRAWAL) RATS TREATED WITH EITHER SAHA OR VEHICLE INJECTION. SINGLE-UNIT RECORDINGS WERE USED TO MEASURE THE RESPONSE OF VTA NEURONS TO GABA. IMMUNOHISTOCHEMISTRY WAS PERFORMED TO EXAMINE LEVELS OF HDAC2, ACETYLATED HISTONE H3 LYSINE 9 (ACH3K9), AND GABA(A) RECEPTOR ALPHA1 AND ALPHA5 SUBUNITS IN THE VTA; QUANTITATIVE POLYMERASE CHAIN REACTION WAS PERFORMED TO EXAMINE THE MRNA LEVELS OF HDAC2 AND GABA(A) RECEPTOR SUBUNITS. RESULTS: VTA NEURONS FROM THE WITHDRAWAL GROUP EXHIBITED GABA HYPOSENSITIVITY. IN VIVO SAHA TREATMENT 2 HOURS BEFORE SACRIFICE NORMALIZED THE SENSITIVITY OF VTA NEURONS TO GABA. ETOH WITHDRAWAL WAS ASSOCIATED WITH INCREASED HDAC2 AND DECREASED ACH3K9 PROTEIN LEVELS; SAHA TREATMENT NORMALIZED ACH3K9 LEVELS. INTERESTINGLY, NO SIGNIFICANT CHANGE WAS OBSERVED IN THE MRNA LEVELS OF HDAC2. THE MRNA LEVELS, BUT NOT PROTEIN LEVELS, OF GABA(A) RECEPTOR ALPHA1 AND ALPHA5 SUBUNITS WERE INCREASED DURING WITHDRAWAL. CONCLUSIONS: WITHDRAWAL FROM CHRONIC ETOH EXPOSURE RESULTS IN A DECREASE IN GABA-MEDIATED INHIBITION, AND THIS GABA HYPOSENSITIVITY IS NORMALIZED BY IN VIVO SAHA TREATMENT. DISRUPTION OF SIGNALING IN THE VTA PRODUCED BY ALTERATION OF GABA NEUROTRANSMISSION COULD BE 1 NEUROADAPTIVE PHYSIOLOGICAL PROCESS LEADING TO CRAVING AND RELAPSE. THESE RESULTS SUGGEST THAT HDACI PHARMACOTHERAPY WITH AGENTS LIKE SAHA MIGHT BE AN EFFECTIVE TREATMENT FOR ALCOHOLISM. 2018